Methods for making 2-(ω-alkoxycarbonylalkanoyl)-4-butanolide, ester of ω-hydroxy-(ω-3)-ketoaliphatic acid, and derivatives thereof

ABSTRACT

In industrial production of ω-hydroxyaliphatic acid being an important intermediate for large cyclic lactone-based perfumes, using dicarboxylate ester which is inexpensive and readily obtainable, a method, with high yield and improved selectively, for making a 2-(ω-alkoxycarbonylalkanoyl)-4-butanolide and an alkaline metal salt thereof, an ester of ω-hydroxy-(ω-3)-ketoaliphatic acid as a novel compound and a derivative thereof, and a method for making the same are provided. 
     Condensation reaction of γ-butyrolactone with a dicarboxylate ester represented by the general formula (1) ROOC(CH 2 )nCOOR wherein n is an integer of 7 to 13 and R is an alkyl group forms a condensation solution containing an alkaline metal salt of 2-(ω-alkoxycarbonylalkanoyl)-4-butanolide represented by the general formula (3):                    
     wherein n is an integer of 7 to 13, R is an alkyl group, and M is an alkaline metal; the solution is extracted with water or an aqueous alkaline solution and subjected to hydrolysis and decarboxylation to form an alkaline metal salt of ω-hydroxy-(ω-3)-ketoaliphatic acid represented by the general formula (5):                    
     wherein n is an integer of 7 to 13 and M is an alkaline metal; and the compound is selectively and effectively separated and recovered and then acidified to form an ω-hydroxy-(ω-3)-ketoaliphatic acid represented by the general formula (10):                    
     wherein n is an integer of 7 to 13.

This application is a divisional of application Ser. No. 09/894,014,filed on Jun. 28, 2001 now U.S. Pat. No. 6,475,133, which is adivisional of application Ser. No. 09/242,805, filed on Feb. 24, 1992now U.S. Pat. No. 6,291,688, which is a 371 of PCT/JP98/02930, filed onJun. 30, 1998, incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to methods for making2-(ω-alkoxycarbonylalkanoyl)-4-butanolide and derivatives thereof, novelesters of ω-hydroxy-(ω-3)-ketoaliphatic acid and derivatives thereof,which are useful as a variety of synthetic raw materials andintermediates, and are prepared as intermediates in the production stepof ω-hydroxyaliphatic acid being important intermediates of large cycliclactone-based perfumes in the perfume industry.

The present invention also relates to a method for separating andpurifying an alkaline metal salt of2-(ω-alkoxycarbonylalkanoyl)-4-butanolide and derivatives thereof, andunreacted dicarboxylic ester, in the production of ω-hydroxyaliphaticacid, being an important intermediate of the large cyclic lactone-basedperfume.

Furthermore, the present invention relates to a method for separatingand recovering ω-hydroxy-(ω-3)-ketoaliphatic acid and salts thereof,dicarboxylic acid and salts thereof, andα,ω-dihydroxy-δ,(ω-3)-alkanedione, in the production ofω-hydroxyaliphatic acid, being an important intermediate of the largecyclic lactone-based perfume.

BACKGROUND ART

Alkaline metal salts of ω-hydroxy-(ω-3)-ketoaliphatic acid representedby the general formula (5):

(wherein n is an integer of 7 to 13, and M indicates an alkaline metal),and ω-hydroxy-(ω-3)-ketoaliphatic acids represented by the generalformula (10):

(wherein n is an integer of 7 to 13) are useful as a variety ofsynthetic raw materials and intermediates and are particularly importantintermediates for macro cyclic lactone-based perfumes in the perfumeindustry.

2-(ω-Alkoxycarbonylalkanoyl)-4-butanolide is useful as a variety ofsynthetic raw materials and intermediates and is effectively used as anintermediate in the production of the above-mentioned ω-hydroxyaliphaticacid, which is a particularly important intermediate for large cycliclactone-based perfumes, such as cyclopentadecanolide andcyclohexadecanolide, in the perfume industry.

Among conventional synthesizing processes for ω-hydroxyaliphatic acid, amethod using ω-cyanoundecanoate ester and γ-butyrolactone as startingmaterials is disclosed in Japanese Patent Application Laid-Open No. Hei5-86013.

In this method, however, raw materials are generally difficult toprepare, and relatively expensive methyl 11-cyanoundecanoate is used asa raw material. Furthermore, ammonia formed in the final carboxylationstep of the nitrile group at the ω-position requires a complicatedprocedure and adversely affects the scent of the final product; hencethis method is still industrially unsatisfactory.

Other synthesizing methods for ω-hydroxyaliphatic acid usingα-(ω-cyanoalkanoyl)-γ-butyrolactone as a starting material are disclosedin Japanese Patent Application Laid-Open Nos. 3-11036 and 5-86013. As anadvantage of these methods, the intermediate, ω-hydroxyketonitrile,which is prepared by hydrolysis and decarboxylation ofα-(ω-cyanoalkanoyl)-γ-butyrolactone in the presence of an alkaline metalhydroxide, is oil-soluble; hence a large amount of water used andalkaline metal carbonate formed as a byproduct are easily separable.

Starting materials for α-(ω-cyanoalkanoyl)-γ-butyrolactone, however, aredifficult to obtain. When relatively expensive a ω-cyanoundecanoateester is used as a raw material or when the nitrile group at theω-position is finally carboxylated, ammonia forms. Thus, a complicatedprocess is required and ammonia adversely affects the scent of the finalproduct; hence, this method is still industrially unsatisfactory.

PCT Patent Application Laid-Open No. WO97-06156 discloses a method usinga significantly readily obtainable and inexpensive dicarboxylate esterrepresented by the general formula ROOC(CH₂)_(n)COOR, wherein n is aninteger of 7 to 13 and R is an alkyl group, and γ-butyrolactone asstarting materials. In this method, an excess of dicarboxylate ester ismixed with γ-butyrolactone in the presence of a basic condensing agentat room temperature and is heated and stirred under normal pressurewhile removing methanol formed in the reaction to prepare2-(ω-alkoxycarbonylalkanoyl)-4-butanolide. This method is alsoexcellent.

The selectivity and yield, however, is still unsatisfactory.Furthermore, a large excess of aqueous alkaline solution must be addedduring hydrolysis and decarboxylation of the intermediate,2-(ω-alkoxycarbonylalkanoyl)-4-butanolide. Thus, a disadvantage of themethod is removal of the large amount of water by distillation beforethe subsequent Wolff-Kishner reduction step.

In this method, an excess of dicarboxylate ester which is two times ormore the fed amount of γ-butyrolactone is used to increase theselectivity on the basis of the dicarboxylate ester raw materialrepresented by the above-mentioned general formula, and unreacteddicarboxylate ester is recovered from the reaction mixture to reuse inthe next reaction.

In the separation of the unreacted dicarboxylate ester and2-(ω-alkoxycarbonylalkanoyl)-4-butanolide after the reaction, afteracidification of the condensation solution, extraction with a solventsuch as ethyl acetate, washing, and recovery of the solvent, thereaction mixture is subjected to simple distillation so that theunreacted dicarboxylate ester in the distilled section is separated fromthe condensation product, 2-(ω-alkoxycarbonylalkanoyl)-4-butanolide, inthe distillation residue.

This method, however, requires a complicated process including manysteps, such as extraction and simple distillation, and has a problem ofdecomposition of 2-(ω-alkoxycarbonylalkanoyl)-4-butanolide in thedistillation. Furthermore, in the subsequent alkaline hydrolysis,decarboxylation, and Wolff-Kishner reduction, the method requires acomplicated step in which alkaline is readded to2-(ω-alkoxycarbonylalkanoyl)-4-butanolide obtained by the acidification.

Japanese Patent Application Laid-Open No. Hei 4-134047 discloses amethod for separating three types of mixtures, that is,ω-hydroxyaliphatic acid or its ester, α-ω-diol, and dicarboxylic acid orits ester, but does not suggest a compound having a carbonyl group inthe molecule.

DISCLOSURE OF THE INVENTION

The present inventors have intensively researched solutions to theproblems in the method disclosed in the PCT Patent Application Laid-OpenNo. WO97-06156, that is, the use of a large amount of aqueous alkalinesolution and a large amount of heat, and the laborious steps forseparating water, and have discovered that these problems may be solvedby using a novel compound, an ester of ω-hydroxy-(ω-3)-ketoaliphaticacid, as an intermediate in the production of ω-hydroxyaliphatic acid,and have thereby completed the present invention.

It is an object of the present invention to provide methods, with highyield, improved selectively, and industrial advantages, for making2-(ω-alkoxycarbonylalkanoyl)-4-butanolide and its derivatives, such asan alkaline metal salt, using readily obtainable and inexpensivedicarboxylate ester.

The present inventors have also discovered a method for effectivelyseparating the condensation products, alkaline metal of2-(ω-alkoxycarbonylalkanoyl)-4-butanolide and its derivative from theunreacted ester by extraction using an inactive solvent with water or anaqueous alkaline solution or by solid-liquid separation using aninactive solvent in the separation of the reaction product and theunreacted dicarboxylate ester from the condensation solution which isprepared from γ-butyrolactone and an excess of dicarboxylate ester inthe presence of a base, and have completed the present invention.

It is another object of the present invention to provide a novelcompound, ester of ω-hydroxy-(ω-3)-ketoaliphatic acid, which isadvantageously used as an intermediate in the industrial production ofω-hydroxyaliphatic acid being an important intermediate for a largecyclic lactone-based perfume, and to provide a method for producing withhigh yield the ester of ω-hydroxy-(ω-3)-ketoaliphatic acid andderivatives thereof.

It is a further object of the present invention to provide a method forseparating and recovering highly selectivelyω-hydroxy-(ω-3)-ketoaliphatic acid and salts thereof, dicarboxylic acidand salts thereof as byproducts, and α,ω-dihydroxy-δ,(ω-3)-alkanedione,in the industrial production of ω-hydroxyaliphatic acid, being animportant intermediate for a large cyclic lactone-based perfume.

The present invention, for achieving the above-mentioned objects,provides a method for making 2-(ω-alkoxycarbonylalkanoyl)-4-butanoliderepresented by the general formula (2) and an alkaline metal salt of the2-(ω-alkoxycarbonylalkanoyl)-4-butanolide represented by the generalformula (3) comprising condensation reaction of γ-butyrolactone with adicarboxylate ester represented by the general formula (1):

ROOC(CH₂)nCOOR  (1)

wherein n is an integer of 7 to 13 and R is an alkyl group;

wherein n is an integer of 7 to 13 and R is an alkyl group;

wherein n is an integer of 7 to 13, R is an alkyl group, and M is analkaline metal,

wherein the dicarboxylate ester represented by the general formula (1)is heated and stirred, and γ-butyrolactone and an alkaline metalalcoholate are added to perform the condensation reaction.

In preferred embodiments, R in the general formula (1) is an alkyl grouphaving 1 to 6 carbon atoms, the condensation reaction is performed whileremoving alcohol by distillation under reduced pressure, and thecondensation reaction is performed by varying the reduced pressure bytwo stages or more.

The alkaline metal salt of the 2-(ω-alkoxycarbonylalkanoyl)-4-butanolideproduced by the foregoing step and represented by the general formula(3) and the unreacted dicarboxylate ester are separated from each otherand purified. A method in accordance with the present invention forseparating and purifying an alkaline metal salt of2-(ω-alkoxycarbonylalkanoyl)-4-butanolide represented by the generalformula (3) and unreacted dicarboxylate ester from a condensationsolution of γ-butyrolactone and the dicarboxylate ester represented bythe general formula (1) comprises solid-liquid separation using asolvent unreactive to the alkaline metal salt of2-(ω-alkoxycarbonylalkanoyl)-4-butanolide.

Another method in accordance with the present invention for separatingand purifying an alkaline metal salt of2-(ω-alkoxycarbonylalkanoyl)-4-butanolide represented by the generalformula (3), a derivative thereof being an alkaline metal salt ofω-hydroxy-(ω-2)-carboxy-(ω-3)-ketoaliphatic acid represented by thegeneral formula (4), an alkaline metal salt ofω-hydroxy-(ω-3)-ketoaliphatic acid represented by the general formula(5), an alkaline metal salt ofω-hydroxy-(ω-2)-carboxy-(ω-3)-ketoaliphatic acid ester represented bythe general formula (6), and an unreacted dicarboxylate ester from acondensation solution of γ-butyrolactone and a dicarboxylate esterrepresented by the above-mentioned general formula (1) comprisesextraction using water or an aqueous alkaline solution:

wherein n is an integer of 7 to 13 and M is an alkaline metal;

wherein n is an integer of 7 to 13 and M is an alkaline metal; and

wherein n is an integer of 7 to 13, R is an alkyl group, and M is analkaline metal. The compounds represented by the general formulae (3),(4), (5) and (6) may be extracted using an inactive solvent with wateror an aqueous alkaline solution.

Also, in the present invention, an ester ofω-hydroxy-(ω-3)-ketoaliphatic acid represented by the general formula(7) is produced:

wherein n is an integer of 7 to 13 and R is an alkyl group.

A method in accordance with the present invention for producing an esterof ω-hydroxy-(ω-3)-ketoaliphatic acid comprises selective hydrolysis anddecarboxylation of the γ-butyrolactone portion of an alkaline metal saltof 2-(ω-alkoxycarbonylalkanoyl)-4-butanolide represented by the generalformula (3):

wherein n is an integer of 7 to 13, R is an alkyl group, and M is analkaline metal. In the present invention, the ester ofω-hydroxy-(ω-3)-ketoaliphatic acid is obtainable by hydrolysis anddecarboxylation of an alkaline metal salt of2-(ω-alkoxycarbonylalkanoyl)-4-butanolide represented by the generalformula (3) in the presence of a weak acid:

wherein n is an integer of 7 to 13, R is an alkyl group, and M is analkaline metal.

The ester of ω-hydroxy-(ω-3)-ketoaliphatic acid represented by thegeneral formula (7) obtained in the present invention is a novelcompound:

wherein n is 10 or 11, and R is an alkyl group. R in the general formula(7) is preferably an alkyl group having 1 to 6 carbon atoms.

In the present invention, α,ω-dihydroxy-δ,(ω-3)-alkanedione representedby the general formula (9) is recovered by adding a required amount ofalkaline to a mixture containing the compounds represented by thegeneral formulae (3), (4), (5) and (6) separated from the condensationsolution for hydrolysis and decarboxylation, and then by extracting theα,ω-dihydroxy-δ,(ω-3)-alkanedione represented by the general formula (9)with an organic solvent from a mixture containing three compounds, analkaline metal salt of ω-hydroxy-(ω-3)-ketoaliphatic acid represented bythe general formula (5), an alkaline metal salt of a long-chaindicarboxylic acid represented by the general formula (8), and theα,ω-dihydroxy-δ,(ω-3)-alkanedione represented by the general formula(9), or by selectively crystallizing theα,ω-dihydroxy-δ,(ω-3)-alkanedione represented by the general formula (9)from the mixture:

wherein n is an integer of 7 to 13 and M is an alkaline metal;

wherein n is an integer of 7 to 13 and M is an alkaline metal;

wherein n is an integer of 7 to 13.

In the present invention, the alkaline metal salt of theω-hydroxy-(ω-3)-ketoaliphatic acid represented by the general formula(5) is selectively crystallized from the mixture containing the alkalinemetal salt of the ω-hydroxy-(ω-3)-ketoaliphatic acid represented by thegeneral formula (5) and the alkaline metal salt of long-chaindicarboxylic acid represented by the general formula (8), and these areseparated into a cake and a filtrate by solid-liquid separation toseparate and recover the alkaline metal salt ofω-hydroxy-(ω-3)-ketoaliphatic acid represented by the general formula(5) and the alkaline metal salt of long-chain dicarboxylic acidrepresented by the general formula (8):

wherein n is an integer of 7 to 13 and M is an alkaline metal;

wherein n is an integer of 7 to 13 and M is an alkaline metal.

Adjusting the pH value of the mixture containing theω-hydroxy-(ω-3)-ketoaliphatic acid represented by the general formula(5) to 5 to 7 with a mineral acid permits separation and recovery ofω-hydroxy-(ω-3)-ketoaliphatic acid represented by the general formula(10) and the alkaline metal salt of long-chain dicarboxylic acidrepresented by the general formula (8):

wherein n is an integer up to 13.

In addition, adjusting the pH value of the filtrate containing thealkaline metal salt of long-chain dicarboxylic acid represented by thegeneral formula (8) to 3 to 5 with a mineral acid permits separation andrecovery of a long-chain dicarboxylic acid represented by the generalformula (11):

wherein n is an integer up to 13.

The target of the present invention is also achieved by a combination ofthese methods.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present invention, γ-butyrolactone is first allowed to react bycondensation with a dicarboxylate ester represented by the generalformula (1) to form 2-(ω-alkoxycarbonylalkanoyl)-4-butanoliderepresented by the general formula (2) or an alkaline metal salt of2-(ω-alkoxycarbonylalkanoyl)-4-butanolide represented by the generalformula (3):

ROOC(CH₂)nCOOR  (1)

wherein n is an integer of 7 to 13 and R is an alkyl group;

wherein n is an integer of 7 to 13 and R is an alkyl group;

wherein n is an integer of 7 to 13, R is an alkyl group, and M is analkaline metal.

The condensation reaction of dicarboxylate ester and γ-butyrolactone inthe presence of a basic condensation agent is complicated; hence, it ispresumed that the selectivity and yield greatly depend on the reactionprocess, such as the method for feeding raw materials and the method forremoving methanol formed. As a result of intensive research by thepresent inventors on the point aimed at the reaction mechanism regardingthe formation of alcohol, it was discovered that2-(ω-alkoxycarbonylalkanoyl)-4-butanolide and its alkaline metal saltare obtained with satisfactory selectivity and yield, as will bedescribed below.

In the first stage, γ-butyrolactone and an alkaline metal alcoholate areadded as droplets to a hot dicarboxylate ester while stirring underreduced pressure which is sufficient to evaporate a formed alcohol toallow the reaction to proceed while distilling the alcohol from thesystem. In the second stage, heating with stirring is continued under afurther reduced pressure to allow the reaction to proceed whiledistilling the alcohol from the system. It was discovered that2-(ω-alkoxycarbonylalkanoyl)-4-butanolide and its alkaline metal saltare obtained with satisfactory selectivity and yield by such stages.

Accordingly, a characteristic feature of the present invention isaddition of γ-butyrolactone and an alkaline metal alcoholate to a hotdicarboxylate ester while stirring to allow condensation reaction. Inthis case, the γ-butyrolactone and the alkaline metal alcoholate may beadded as a mixture or independently.

It is preferable that the reaction be performed while distilling alcoholfrom the system. In addition, it is preferable in view of furthersatisfactory selectivity and yield that the reaction be continued whiledistilling the residual alcohol from the system under further reducedpressure.

R in the dicarboxylate ester represented by dicarboxylate esterrepresented by the general formula (1), ROOC(CH₂)nCOOR wherein n is aninteger of 7 to 13 and R is an alkyl group, is preferably an alkyl grouphaving 1 to 6 carbon atoms, in view of convenience of use.

Examples of R include methyl, ethyl, propyl, butyl, isobutyl, pentyl,and hexyl groups. Among these, methyl is preferable.

Examples of preferable dicarboxylate esters represented by the generalformula (1) include dimethyl 1,12-dodecanedicarboxylate and dimethyl1,13-tridecanedicarboxylate (dimethyl brassylate).

In the present invention, the condensation reaction proceeds in thepresence of an alkaline metal alcoholate. Preferable alkaline metalalcoholates are represented by the general formula R′OM wherein R′ is analkyl group having 1 to 4 carbon atoms and M is an alkaline metal.

Examples of the alkaline metal alcoholates include sodium methylate,sodium ethylate, sodium propylate, sodium butylate, potassium methylate,potassium ethylate, potassium propylate, and potassium butylate.

Although the amount of the alkaline metal alcoholate used in the presentinvention is not limited, the amount is preferably 0.1 to 5 equivalentsand more preferably 0.5 to 3 equivalents with respect toγ-butyrolactone. When the amount of alkaline metal alcoholate used issmall, the yield will decrease. When the amount used is higher than thepredetermined level, the selectivity may decrease.

It is preferable in the present invention that the dicarboxylate esterrepresented by the general formula (1) be used in an excess amount on amolar basis to γ-butyrolactone, and particularly 2 times or more bymole. The use of the dicarboxylate ester in an amount of 2 times or moreby mole results in a particular improvement in selectivity.

If unreacted dicarboxylate ester is present when the present inventionis executed, it is preferable in view of effective reaction that theunreacted dicarboxylate ester be recovered from the reaction mixture torecycle it to the condensation reaction. In the present invention, theunreacted dicarboxylate ester can be readily recovered from the reactionmixture by extraction with water or an aqueous alkaline solution or bysolid-liquid separation; hence a combination of the excessive use andrecycling use of the dicarboxylate ester permits more effectivereaction.

The condensation reaction in the present invention is preferablyperformed under reduced pressure to effectively remove alcohol. Apreferable reduced pressure is in a range of 50 to 760 mmHg, and morepreferably 100 to 600 mmHg. The pressure may be diminished by two ormore stages. For example, the pressure during the reaction is diminishedto approximately 500 to 700 mmHg which is sufficient for distillation ofalcohol in the first stage, and then further diminished to approximately50 to 300 mmHg in the second stage.

Although the heating temperature in the condensation reaction is notlimited, a preferable condition is set in relation to the reducedpressure. A preferable temperature lies in a range of 30 to 200° C., andmore preferably 50 to 150° C.

Although no solvent is required in the present invention, a solvent usedin general ester condensation may be used in this reaction as long as itdoes not decrease the activity of the alkaline metal alcoholate.

The reaction in accordance with the present invention may be performedby a batch system, a continuous system, or a multistage system.

The alkaline metal salt of 2-(ω-alkoxycarbonylalkanoyl)-4-butanolideobtained in the present invention can be readily converted with highyield into ω-hydroxyaliphatic acid, which is an important intermediatefor a large cyclic lactone-based perfume, as will be described later.

The product of the condensation reaction of the dicarboxylate esterrepresented by the general formula (1) with γ-butyrolactone is aβ-ketoester type compound which is generally present as an alkaline saltrepresented by the general formula (3) in the reaction solution:

wherein n is an integer of 7 to 13, R is an alkyl group, and M is analkaline metal. It was discovered that the alkaline metal saltrepresented by the general formula (3) has significantly lowersolubility in an organic solvent such as n-hexane. The salt is readilysoluble in an aqueous alkaline solution. The γ-butyrolactone portion andthe ester terminal are rapidly hydrolyzed to form an alkaline metal saltof dicarboxylic acid represented by the general formula (4), and thesalt is partly decarboxylated to form an alkaline metal salt representedby the general formula (5) when a certain amount of alkaline metalhydroxide is added:

wherein n is an integer of 7 to 13 and M is an alkaline metal;

In contrast, the dicarboxylate ester represented by the general formula(1) used in excess in the condensation reaction of the present inventionremains without reaction in the solution. The compound is significantlysoluble in an organic solvent such as n-hexane.

Accordingly, the present inventors have intensively studied solubilityof the alkaline metal salt of 2-(ω-alkoxycarbonylalkanoyl)-4-butanolidein organic solvents and water, have discovered a purification method forindependently recovering the alkaline metal salt of2-(ω-alkoxycarbonylalkanoyl)-4-butanolide with its derivative, and theunreacted dicarboxylate ester with ease and high yield, and havecompleted the present invention.

The method in the present invention separates the alkaline metal saltrepresented by the general formula (3) and the unreacted dicarboxylateester represented by the general formula (1) by solid-liquid separationsuch as filtration (hereinafter referred to as a solid-liquid separationmethod).

An organic solvent, which can dissolve the unreacted dicarboxylate esterand is unreactive to the alkali and the alkaline metal salt of2-(ω-alkoxycarbonylalkanoyl)-4-butanolide, is added to the condensationsolution to sufficiently dissolve the unreacted dicarboxylate ester andto form a salt suspension. The suspension is separated into a liquidcomponent and a solid component by any known method such as filtrationor centrifugal separation. The solid component is thoroughly washed withthe solvent to remove the unreacted dicarboxylate ester. The liquidcomponent and the washings are concentrated together and recycled to thenext condensation reaction.

On the other hand, the solid component can be used without furthertreatment or after converting it into2-(ω-alkoxycarbonylalkanoyl)-4-butanolide by acidification. It can alsobe used for hydrolysis and decarboxylation in an aqueous alkalinesolution.

The present invention also relates to a method for extracting the saltof 2-(ω-alkoxycarbonylalkanoyl)-4-butanolide with water and theunreacted dicarboxylate ester with an organic solvent for separationthereof (hereinafter referred to as an alkaline extraction method).

Water or an aqueous alkaline solution is added to the condensationsolution to dissolve the alkaline metal salt of2-(ω-alkoxycarbonylalkanoyl)-4-butanolide, the unreacted dicarboxylateester is recovered into an organic layer from the mixture by aseparative operation, and then washed with water to recycle it for thenext condensation reaction.

On the other hand, the aqueous layer contains the alkaline metal saltrepresented by the general formula (3), the compound represented by thegeneral formula (6), the alkaline metal salt represented by the generalformula (4) in the case of addition of a given amount of alkaline metalhydroxide, and the alkaline metal slat represented by the generalformula (5) formed by partial decarboxylation in the case of addition ofa given amount of alkaline metal hydroxide. This phenomenon wasclarified by determining the composition of the crystal extract afteracidification of the aqueous layer obtained by the above-mentionedoperation.

It was found that the crystal extract primarily contains the compoundrepresented by the general formula (2), long-chain dicarboxylic acid,2-(ω-carboxyundecanoyl)-4-butanolide represented by the general formula(12), and ω-hydroxy-(ω-3)-ketoaliphatic acid represented by the generalformula (10):

wherein n is an integer of 7 to 13;

wherein n is an integer of 7 to 13.

It is presumed in the present invention that the crystal extractcontains the 2-(ω-alkoxycarbonylalkanoyl)-4-butanolide represented bythe general formula (2) and the 2-(ω-carboxyundecanoyl)-4-butanoliderepresented by the general formula (12) for the following reason. Whenthe alkaline metal salt represented by the general formula (3) isdissolved in an aqueous alkaline solution, the γ-butyrolactone portionis rapidly hydrolyzed to form the compound represented by the generalformula (6).

Acidification of the extract forms a compound represented by the generalformula (13):

wherein n is an integer of 7 to 13. The product is rapidly dehydrated toform a lactone ring and thus the compound represented by the generalformula (2). When a given amount of alkaline is added, the terminalester group in the general formula (6) is also presumably hydrolyzed toform the alkaline metal salt of dicarboxylic acid represented by thegeneral formula (4).

Acidification of the compound represented by the general formula (4)forms a dicarboxylic acid represented by the general formula (14):

wherein n is an integer of 7 to 13. The product is rapidly dehydrated toform a lactone ring and thus 2-(ω-carboxyundecanoyl)-4-butanoliderepresented by the general formula (12).

The formation of ω-hydroxy-(ω-3)-ketoaliphatic acid is caused bydecarboxylation of the β-ketoacid occurring when the amount of thealkaline metal salt is in excess with respect to hydrolysis.

The resulting aqueous layer can be used for the subsequent hydrolysisand decarboxylation.

Solvents used in the present invention are not limited as long as theyare unreactive to the alkali and the salt of2-(ω-alkoxycarbonylalkanoyl)-4-butanolide. Examples of such solventsinclude organic solvents, such as pentane, hexane, heptane, octane,cyclohexane, benzene, toluene, xylene, diethylether, and isopropylether.

Although the alkaline extraction method can be achieved without using asolvent, the use of a solvent is preferable. The amount of the solventis preferably 0 to 10 times by weight, and more preferably 0.5 to 5times by weight with respect to the condensation solution. Thetemperature of dissolution into the solvent and the temperature of thealkaline extraction are not limited within a range not causingsolidification of the organic solvent, and lie in a range of generally0° C. to 100° C., and preferably 20° C. to 50° C.

The alkaline compounds used in the alkaline extraction in the presentinvention are not limited as long as they can extract2-(ω-alkoxycarbonylalkanoyl)-4-butanolide and its alkaline metal saltand derivative. Examples of usable alkaline compounds include alkalinemetal hydroxide, such as lithium hydroxide, sodium hydroxide, andpotassium hydroxide; alkaline metal carbonates, such as sodium carbonateand potassium carbonate; and alkaline earth metal hydroxides, such asbarium hydroxide.

The concentration of the aqueous alkaline solution is not limited, andlies in a range of preferably 0.5 to 50%, and more preferably 1 to 15%.In addition, the amount is not limited, and lies in a range ofpreferably 0.1 to 10 times by weight and more preferably 0.5 to 2 timesby weight with respect to the condensation solution. The purification inaccordance with the present invention can be performed by either a batchsystem or a continuous system.

Furthermore, the present inventors have discovered that heating of thealkaline metal salt of 2-(ω-alkoxycarbonylalkanoyl)-4-butanolideobtained in the above-described operation with a weak acid such asphosphoric acid forms the ester of ω-hydroxy-(ω-3)-ketoaliphatic acidrepresented by the general formula (7) with high yield:

wherein n is an integer of 7 to 13 and R is an alkyl group. The presentinventors have also discovered that the compound represented by thegeneral formula (7) is oil-soluble and thus can be readily separablefrom the reaction solution, and have completed the present invention.The ester of ω-hydroxyketoaliphatic acid is useful as an intermediate inthe production of ω-hydroxyaliphatic acid which is an importantintermediate for a macro cyclic lactone-based perfume in the perfumeindustry.

Among the esters of ω-hydroxy-(ω-3)-ketoaliphatic acid represented bythe general formula (7), novel compounds are esters ofω-hydroxy-(ω-3)-ketoaliphatic acid wherein n is 10 or 11.

In the present invention, selective hydrolysis and decarboxylation ofthe γ-butyrolactone portion in the alkaline metal salt of2-(ω-alkoxycarbonylalkanoyl)-4-butanolide obtained in theabove-mentioned operation forms the ester ofω-hydroxy-(ω-3)-ketoaliphatic acid represented by the general formula(7):

wherein n is an integer of 7 to 13 and R is an alkyl group. In addition,in the present invention, hydrolysis and decarboxylation of the alkalinemetal salt of 2-(ω-alkoxycarbonylalkanoyl)-4-butanolide represented bythe general formula (3) by heating with a weak acid forms the ester ofω-hydroxy-(ω-3)-ketoaliphatic acid represented by the general formula(7).

Types of the weak acids used in hydrolysis and decarboxylation in thepresent invention are not limited. Examples of weak acids includephosphoric acid, pyrophosphoric acid, and carbonic acid. Sodiumdihydrogen-phosphate and the like are also usable. The amount of theweak acid used is not limited, and lies in a range of 0.5 to 3equivalents, and more preferably 0.5 to 1 equivalents with respect to 1mole of alkaline metal salt of2-(ω-alkoxycarbonylalkanoyl)-4-butanolide.

The amount of water used in the reaction in the present invention is notlimited, and preferably lies in a range of 2 to 20 times with respect tothe alkaline metal salt of 2-(ω-alkoxycarbonylalkanoyl)-4-butanolide.

A water-soluble organic solvent may or may not be used in the hydrolysisand decarboxylation in the present invention. Examples of thewater-soluble organic solvents include methanol, ethanol, diethyleneglycol, triethylene glycol, dioxane, tetrahydrofuran, and1,2-dimethoxyethane. The water-soluble organic solvent is preferablyused in an amount of 0.05 to 3 parts by weight to 1 parts by weight ofwater.

The reaction in accordance with the present invention requires heating.The heating is performed in the presence of a weak acid such asphosphoric acid in the present invention. The heating temperaturepreferably lies in a range of 80 to 110° C. The reaction time isappropriately determined depending on the reaction temperature and fedraw materials, and generally lies in a range of 1 to 20 hours. Thereaction can be performed by a batch system or a continuous system.Isolation and purification of the reaction products can be achieved byany conventional unit operations including liquid separation,extraction, washing and recrystallization.

The ester of ω-hydroxy-(ω-3)-ketoaliphatic acid represented by thegeneral formula (7) obtained in the present invention can be easilyconverted into ω-hydroxy-aliphatic acid as an important intermediate fora macro cyclic lactone-based perfume with high yield and industrialadvantages.

The —COOR group of the ester of ω-hydroxy-(ω-3)-ketoaliphatic acid ishydrolyzed to form the alkaline metal salt ofω-hydroxy-(ω-3)-ketoaliphatic acid represented by the general formula(5) by heating in an aqueous alkaline metal hydroxide solution or amixed solvent of a water-soluble organic solvent and water. The —CO—group is reduced to —CH₂— group by the conventional Wolff-Kishner ketonereduction process, and thus yields ω-hydroxyaliphatic acid. As describedabove, the ester of ω-hydroxyaliphatic acid is useful as a raw syntheticmaterial and as an intermediate, and particularly as an intermediate inthe production of ω-hydroxyaliphatic acid which is an importantintermediate for large cyclic lactone-based perfumes, such ascyclopentadecanolide and cyclohexadecanolide, in the perfume industry.

The present invention relates to separation of the compound representedby the general formula (9) by extraction with an organic solvent orcrystallization, in which the compound is formed by hydrolysis anddecarboxylation of the byproduct in the condensation reaction which ispresent in the reaction mixture after extraction, hydrolysis, anddecarboxylation under a basic condition of the condensation products ofthe above-mentioned dicarboxylate ester and γ-butyrolactone:

wherein n is an integer of 7 to 13. The residual aqueous solution istreated at a predetermined temperature to selectively crystallize thealkaline metal salt of ω-hydroxy-(ω-3)-ketoaliphatic acid, and thensubjected to solid-liquid separation to separate the solution into thecake and the filtrate. The alkaline metal salt ofω-hydroxy-(ω-3)-ketoaliphatic acid represented by the general formula(5) and the alkaline metal salt of dicarboxylic acid represented by thegeneral formula (8) are thereby separately recovered. Alternatively, theresulting cake and filtrate are independently treated with a mineralacid to separately recover the ω-hydroxy-(ω-3)-ketoaliphatic acidrepresented by the general formula (10) and the dicarboxylic acidrepresented by the general formula (11):

wherein n is an integer of 7 to 13;

wherein n is an integer of 7 to 13.

Alternatively, the pH of the mixture containing the alkaline metal saltof ω-hydroxy-(ω-3)-ketoaliphatic acid represented by the general formula(5) and the alkaline metal salt of long-chain dicarboxylic acidrepresented by the general formula (8) is adjusted to 5 to 7 with amineral acid to precipitate the compound represented by the generalformula (10), and is then subjected to solid-liquid separation toseparately recover the ω-hydroxy-(ω-3)-ketoaliphatic acid represented bythe general formula (10) and the alkaline metal salt of long-chaindicarboxylic acid represented by the general formula (8). The pH of thefiltrate is adjusted to 3 to 5, if necessary, to recover the long-chaindicarboxylic acid represented by the general formula (11) byprecipitation and then solid-liquid separation.

For example, the compound represented by the general formula (9) isremoved by extraction from, or selectively crystallized by treatment ata predetermined temperature from, the mixture containing the alkalinemetal salt of ω-hydroxy-(ω-3)-ketoaliphatic acid represented by thegeneral formula (5), the alkaline metal salt of long-chain dicarboxylicacid represented by the general formula (8), and theα,ω-dihydroxy-δ,(ω-3)-alkanedione represented by the general formula(9). Next, the aqueous solution after removing the cake by solid-liquidseparation is treated at a predetermined temperature to selectivelycrystallize the compound represented by the general formula (5) and thenseparated into a cake and a filtrate by solid-liquid separation. Whenthe filtrate contains a small amount of compound represented by thegeneral formula (5), the pH of the filtrate is adjusted to 5 to 7 tocrystallize the compound represented by the general formula (10) and toseparately recover the ω-hydroxy-(ω-3)-ketoaliphatic acid represented bythe general formula (10) and the alkaline metal salt of long-chaindicarboxylic acid represented by the general formula (8) after thesubsequent solid-liquid separation. The pH of the resulting filtrate isadjusted to 3 to 5 to crystallize the compound represented by thegeneral formula (11) and to separately recover the alkaline metal saltof long-chain dicarboxylic acid represented by the general formula (8)after the subsequent solid-liquid separation.

Any organic solvent which is unreactive in basic conditions andinsoluble in water can be used without limitation to separate theα,ω-dihydroxy-δ,(ω-3)-alkanedione represented by the general formula (9)from the reaction mixture. Examples of the organic solvents includebenzene, toluene, xylene, tetralin, decalin, pentane, hexane, heptane,octane, cyclohexane, isopropyl ether, and dibutyl ether. Among them,toluene is preferably used.

The amount of the organic solvent used in the present invention is notlimited, and lies in a range of preferably 0.5 to 20 parts by weight,and more preferably 1 to 10 parts by weight with respect to the reactionmixture in view of processing and material cost.

The extraction temperature of the compound represented by the generalformula (9) is not limited in the present invention, and lies in a rangeof 50 to 110° C., and preferably 60 to 90° C. in view of the boilingpoints of the organic solvent and water used for the extraction;however, the higher the extraction temperature, the higher theextraction efficiency. Although the organic layer may contain thecompound represented by the general formula (5), the compound can besubstantially recovered by reverse extraction with hot water.

Although the crystallization temperature of the compound represented bythe general formula (9) in the present invention significantly dependson the composition of the reaction mixture and particularly the watercontent, it is not limited as long as the compound represented by thegeneral formula (9) is crystallized and the salts represented by thegeneral formulae (5) and (8) are dissolved. The crystallizationtemperature is preferably in a range of −20 to 80° C., and morepreferably 0 to 40° C., in view of processing.

In the crystallization of the compound represented by the generalformula (9), although the water content in the reaction mixture issignificantly affected by the composition and temperature of thereaction mixture, it is not limited as long as the water content permitscrystallyzation of the compound represented by the general formula (9)and dissolution of the salts represented by the general formulae (5) and(8). The water content is preferably in a range of 50 to 99 percent byweight, and more preferably 70 to 90 percent by weight in view ofprocessing.

Solid-liquid separation of the crystal represented by the generalformula (9) in the present invention may be performed by anyconventional method such as centrifugal sedimentation, centrifugalhydroextraction, or filtration. Although the resulting cake may containthe salts represented by the general formulae (5) and (8) in some cases,washing with water enables an increase in purity of the compoundrepresented by the general formula (9) in the cake and recovery of thesalts represented by the general formulae (5) and (8) as an aqueoussolution.

The extraction step in the present invention may be of a batch type or amulti-vessel type, or a continuous type.

The crystallization conditions of the alkaline metal salt ofω-hydroxy-(ω-3)-ketoaliphatic acid represented by the general formula(5) will now be described.

Although the crystallization temperature of the compound represented bythe general formula (5) significantly depends on the composition andparticularly on the water content of the reaction mixture, it is notlimited as long as the crystals of the compound represented by thegeneral formula (5) forms and the compound represented by the generalformula (2) is dissolved. The crystallization temperature is in a rangeof preferably −20 to 80° C., and more preferably 0 to 40° C. in view ofprocessing.

Although the water content in the present invention significantlydepends on the composition and temperature of the reaction mixture, itis not limited as long as the crystals of the compound represented bythe general formula (5) forms and the compound represented by thegeneral formula (8) is dissolved. The water content is in a range ofpreferably 50 to 99 percent by weight, and more preferably 70 to 90percent by weight in view of processing.

The solid-liquid separation of the crystal formed in the presentinvention can be performed by any conventional method, such ascentrifugal sedimentation, centrifugal hydroextraction, or filtration.Although the resulting cake may contain the compound represented by thegeneral formula (8) in some cases, washing with water enables anincrease in purity of the compound represented by the general formula(5) in the cake and recovery of the compound represented by the generalformula (8) as an aqueous solution.

The cake obtained in the production of the large cyclic lactone can beused in the next reductive reaction without further treatment or afteracidification. The reductive reaction can be achieved by a conventionalmethod, such as Wolff-Kishner reduction, or Clemmensen reduction.

The mineral acid used for acidifying the alkaline metal saltsrepresented by the general formulae (5) and (8) is not limited, andsulfuric acid and hydrochloric acid are often used. The aliphatic acidafter the acidification can be recovered by a solid-liquid separationmethod, such as centrifugal sedimentation, centrifugal hydroextraction,or filtration; or extraction with an organic solvent, such as benzene,toluene, xylene, pentane, hexane, heptane, octane, cyclohexane, diethylether, isopropyl ether, ethyl acetate, dichloromethane, chloroform,carbon tetrachloride, or dichloroethane, although the method depends onthe shape of the aliphatic acid.

When the compound represented by the general formula (10) is obtainedfrom the mixture of the compounds represented by the general formulae(5) and (8) with a mineral acid, the pH is preferably in a range of 5 to7, and more preferably 5.5 to 6.5. When the compound represented by thegeneral formula (11) is obtained after acidification of the compoundrepresented by the general formula (8), the pH is preferably in a rangeof 3 to 4, and more preferably 3.5 to 4.5. A further reduction in the pHvalue is not preferable due to an increased amount of mineral acid usedand increased material cost, although the recovery rate and purity ofthe compound represented by the general formula (11) are not affected.

EXAMPLES

The present invention will now be described in more detail withreference to the following EXAMPLES. These EXAMPLES are forexemplification and should not in any way be construed as limitative.

Example 1

Dimethyl 1,12-dodecanedioate (105.00 g, 406.4 mmol) was fed into areaction vessel and was heated to 105° C. while being stirred under areduced pressure of 600 mm Hg. A mixture of γ-butyrolactone (8.75 g,101.6 mmol) and a 28-wt % sodium methoxide in methanol solution (19.60g, 101.6 mmol), which were mixed at room temperature, was added dropwiseto the heated dimethyl 1,12-dodecanedioate over a period of 30 minuteswhile removing methanol by distillation. After the reaction hadproceeded for 30 minutes, the mixture was evacuated to 200 mmHg tocontinue the reaction for further 120 minutes.

The mixture was subjected to normal pressure, cooled, poured into adiluted hydrochloric acid solution, and then extracted with ethylacetate. The organic layer was washed with water, dried with anhydrousmagnesium sulfate, and was distilled to remove the solvent. The oilyresidue was distilled under a reduced pressure (bath temperature: 170 to180° C./0.5 to 0.2 mmHg) to remove the excess dimethyl1,12-dodecanedioate. The resulting products were 81.9 g of the distilledcomponent and 25.1 g of the distillation residue.

According to the results of gas chromatography, the distillation residuecontains 88.6 percent by weight of the compound represented by thegeneral formula (2) (n=10, R=Me). The yield was 80.2% and theselectivity was 83.2%.

Example 2

Dimethyl 1,12-dodecanedioate (105.00 g, 406.4 mmol) was fed into areaction vessel and was heated to 105° C. while being stirred under areduced pressure of 600 mm Hg. A mixture of γ-butyrolactone (8.75 g,101.6 mmol) and a 28-wt % sodium methoxide in methanol solution (19.60g, 101.6 mmol), which were mixed at room temperature, was added dropwiseto the heated dimethyl 1,12-dodecanedioate over a period of 30 minuteswhile removing methanol by distillation. After the reaction hadproceeded for 30 minutes, the mixture was evacuated to 200 mmHg tocontinue the reaction for further 240 minutes.

The mixture was subjected to normal pressure, cooled, poured into adiluted hydrochloric acid solution, and then extracted with ethylacetate. The organic layer was washed with water, dried with anhydrousmagnesium sulfate, and was evaporated to remove the solvent. The oilyresidue was distilled under a reduced pressure (bath temperature: 170 to180° C./0.5 to 0.2 mmHg) to remove the excess dimethyl1,12-dodecanedioate. The resulting products were 82.2 g of the distilledcomponent and 26.5 g of the distillation residue. It was found that thedistillation residue contains 88.1 percent by weight of the compoundrepresented by the general formula (2) (n=10, R=Me). The yield was 81.4%and the selectivity was 87.9%.

Example 3

Dimethyl 1,12-dodecanedioate (105.00 g, 406.4 mmol) was fed into areaction vessel and was heated to 105° C. while being stirred under areduced pressure of 500 mm Hg. A mixture of γ-butyrolactone (8.75 g,101.6 mmol) and a 28-wt % sodium methoxide in methanol solution (19.60g, 101.6 mmol), which were mixed at room temperature, was added dropwiseto the heated dimethyl 1,12-dodecanedioate over a period of 30 minuteswhile removing methanol by distillation. After the reaction hadproceeded for 30 minutes, the mixture was evacuated to 100 mmHg tocontinue the reaction for further 120 minutes.

The mixture was subjected to normal pressure, cooled, poured into adiluted hydrochloric acid solution, and then extracted with ethylacetate. The organic layer was washed with water, dried with anhydrousmagnesium sulfate, and was distilled to remove the solvent. The oilyresidue was distilled under a reduced pressure (bath temperature: 170 to180° C./0.5 to 0.2 mmHg) to remove the excess dimethyl1,12-dodecanedioate. The resulting products were 81.4 g of the distilledcomponent and 27.2 g of the distillation residue. It was found that thedistillation residue contains 88.3 percent by weight of the compoundrepresented by the general formula (2) (n=10, R=Me). The yield was 81.6%and the selectivity was 86.0%.

Comparative Example 1

Dimethyl 1,12-dodecanedioate (105.00 g, 406.4 mmol), γ-butyrolactone(8.75 g, 101.6 mmol), and a 28-wt % sodium methoxide in methanolsolution (19.60 g, 101.6 mmol) were mixed at 50° C., and then heated to110° C. over a period of 45 minutes while removing methanol bydistillation. After the reaction had proceeded for 30 minutes, themixture was evacuated to 630 mmHg to continue the reaction for further30 minutes.

The mixture was subjected to normal pressure, cooled, poured into adiluted hydrochloric acid solution, and then extracted with ethylacetate. The organic layer was washed with water, dried with anhydrousmagnesium sulfate, and was distilled to remove the solvent. The oilyresidue was distilled under a reduced pressure (bath temperature: 170 to180° C./0.5 to 0.2 mmHg) to remove the excess dimethyl1,12-dodecanedioate. The resulting products were 81.5 g of the distilledcomponent and 25.6 g of the distillation residue. It was found that thedistillation residue contains 85.1 percent by weight of the compoundrepresented by the general formula (1) (n=10, R=Me). The yield was 79.0%and the selectivity was 79.0%.

Example 4 Solid-liquid Separation Method

116.2 g of a condensation solution (confirmed by quantitative analysis,after acidification of a part, that the solution contains 25.71 g of thecondensation product and 80.70 g of the unreacted ester) prepared fromdimethyl 1,12-dodecanedioate (105.00 g, 406.4 mmol), γ-butyrolactone(8.75 g, 101.6 mmol), and a 28-wt % sodium methoxide in methanolsolution (19.60 g, 101.6 mmol) was heated to 50° C. while being stirred.Into the solution, 565 g of n-hexane was added, and cooled to 20° C.while being stirred to form a suspension containing a pale yellowprecipitate and a clear supernatant liquid. The suspension was separatedinto a precipitate and a supernatant liquid using a pressure filter. Thecake was thoroughly washed with n-hexane.

The filtrate and the washings were mixed and then n-hexane was removedby distillation to obtain 80.94 of concentrate. According to the gaschromatographic quantitative analysis of the concentrate, it contained99.2% of the compound represented by the general formula (1) (n=10,R=Me). The yield was 99.5%.

After acidifying 1.00 g among 35.35 g of the resulting cake, it wasextracted with ethyl acetate. The organic layer was washed with water,dried with anhydrous sodium sulfate, and was distilled to remove thesolvent. A crystal product in an amount of 0.92 g was thereby obtained.According to gas chromatographic determination, the crystal productcontains 0.73 g of compound represented by the general formula (2)(n=10, R=Me) and 0.01 g of compound represented by the general formula(1) (n=10, R=Me). The recovery of the compound represented by thegeneral formula (2) was 100 percent by weight, and the residual rate ofthe ester of dicarboxylic acid represented by the general formula (1)was 0.4 percent by weight.

Example 5

A condensation solution (confirmed by quantitative analysis, afteracidification of a part, that the solution contains 12.25 g of thecondensation product and 42.61 g of the unreacted ester) prepared fromdimethyl 1,12-dodecanedioate (64.73 g, 207.2 mmol), γ-butyrolactone(4.46 g, 51.8 mmol), and a 28-wt % sodium methoxide in methanol solution(9.99 g, 51.8 mmol) was heated to 50° C. while being stirred. Into thesolution, 50.0 g of n-hexane was added, and the solution was stirred for2 minutes. Next, 50.0 g of water was added while continuing stirring for30 minutes. The organic layer was washed with water and concentrated. Asa result, 44.31 g of a crystalline product containing 94.1% of compoundrepresented by the general formula (1) (n=10, R=Me) was obtained. Therecovery was 97.9%.

The aqueous layer was immediately poured into diluted sulfuric acid toacidify the layer, and was extracted with ethyl acetate, followed bywashing with water. The solution was dried with anhydrous sodium sulfateand then the solvent was removed by distillation. According to gaschromatographic determination, 13.11 g of the resulting crystal contains71% of the compound represented by the general formula (2) (n=10, R=Me).The recovery was 78.2%.

Example 6 Alkaline Extraction Method

A condensation solution (confirmed by quantitative analysis, afteracidification of a part, that the solution contains 25.49 g of thecondensation product and 80.82 g of the unreacted ester) prepared fromdimethyl 1,12-dodecanedioate (105.00 g, 406.4 mmol), γ-butyrolactone(8.75 g, 101.6 mmol), and a 28-wt % sodium methoxide in methanolsolution (19.60 g, 101.6 mmol) was heated to 50° C. while being stirred.Into the solution, 104.4 g of n-hexane was added, and the solution wasstirred for 2 minutes. Next, 107.5 g of an aqueous 5%-KOH solution wasadded while continuing stirring for 120 minutes. After allowing it tostand for 5 minutes, the mixture was separated into an organic layer andan aqueous layer. The organic layer was washed with water andconcentrated. As a result, 80.9 g of a crystalline product containing98.8% (observed value) of a compound represented by the general formula(1) (n=10, R=Me) was obtained. The recovery was 98.9%.

The aqueous layer was immediately poured into diluted sulfuric acid toacidify the layer, and was extracted with ethyl acetate, followed bywashing with water. The solution was dried with anhydrous sodiumsulfate, and then the solvent was removed by distillation. According togas chromatographic determination, the resulting crystal contains 23.1%of the compound represented by the general formula (10) (n=10). Acolorless crystal (0.61 g) prepared by silica-gel chromatographicfractionation of 1.00 g of the crystal was identified by IR and NMR, anda compound represented by the general formula (12) (n=10) was confirmed.

Example 7 Alkaline Extraction Method

A condensation solution (confirmed by quantitative analysis, afteracidification of a part, that the solution contains 25.58 g of thecondensation product and 80.56 g of the unreacted ester) prepared fromdimethyl 1,12-dodecanedioate (105.00 g, 406.4 mmol), γ-butyrolactone(8.75 g, 101.6 mmol), and a 28-wt % sodium methoxide in methanolsolution (19.60 g, 101.6 mmol) was heated to 50° C. while being stirred.Into the solution, 139.7 g of cyclohexane was added, and the solutionwas stirred for 2 minutes. Next, 143.9 g of an aqueous 5%-KOH solutionwas added while continuing stirring for 10 minutes. After allowing it tostand for 5 minutes, the mixture was separated into an organic layer andan aqueous layer. The organic layer was washed with water andconcentrated. As a result, 81.62 g of a crystalline product containing98.9% (observed value) of a compound represented by the general formula(1) (n=10, R=Me) was obtained. The recovery was 100.0%.

Reference Example 1

Into the aqueous layer obtained in EXAMPLE 3, 23.3 g of an aqueous49%-KOH solution was added followed by reflux for 2 hours. Afteracidification with diluted sulfuric acid, the solution was extractedwith ethyl acetate. The organic layer was washed with water and driedwith anhydrous sodium sulfate, and then the solvent was removed bydistillation to obtain 27.50 g of crude crystal. According to gaschromatographic determination, the crystal contains 80.2 percent byweight of a compound represented by the general formula (10) (n=10). Theyield of the compound represented by the general formula (2) (n=10,R=Me) from the condensation solution was 99.0%.

Comparative Example 2

A condensation solution (confirmed by quantitative analysis, afteracidification of a part, that the solution contains 25.68 g of thecondensation product and 80.67 g of the unreacted ester) prepared fromdimethyl 1,12-dodecanedioate (105.00 g, 406.4 mmol), γ-butyrolactone(8.75 g, 101.6 mmol), and a 28-wt % sodium methoxide in methanolsolution (19.60 g, 101.6 mmol) was extracted with ethyl acetate afterpouring into diluted hydrochloric acid. The organic layer was washedwith water and dried with anhydrous magnesium sulfate, and then thesolvent was removed by distillation. The resulting oily residue wasdistilled under reduced pressure (bath temperature: 170 to 180° C./0.5to 0.2 mmHg) to remove the excess dimethyl 1,2-dodecanedioate. As aresult, 802 g of an evacuated component and 31.55 g of the residue wereobtained. According to gas chromatographic determination, the evacuatedcomponent contains 98.3% of a compound represented by the generalformula (1) (n=10, R=Me). The yield was 98%.

The distillation residue (2.00 g) was acidified followed by extractionwith ethyl acetate. The organic layer was washed with water and driedwith anhydrous sodium sulfate, and then the solvent was removed bydistillation. A crystal product in an amount of 1.88 g was obtained.According to gas chromatographic determination, the crystal productcontains 84.0 percent by weight of a compound represented by the generalformula (5) (n=10, R=Me). The purified yield was 97.00%.

Next, 2.00 g of the distillation residue, sodium hydroxide (1.75 g, 13.7mmol), 40 g of water, and 20 g of methanol were mixed and fluxed whilebeing heated for 4 hours. After cooling and acidifying, the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand dried with anhydrous sodium sulfate, and the solvent was distilled.As a result, 1.57 g of a crude crystal product was obtained. Accordingto gas chromatographic determination, the product contains 86.6 percentby weight of a compound represented by the general formula (10) (n=10).The yield was 95 mol percent with regard to the compound represented bythe general formula (2).

Example 8

A condensation solution in an amount of 113.2 g (confirmed byquantitative analysis, after acidification of a part, that the solutioncontains 25.65 g of the condensation product and 80.84 g of theunreacted ester) prepared from dimethyl 1,12-dodecanedioate (105.00 g,406.4 mmol), γ-butyrolactone (8.75 g, 101.6 mmol), and a 28-wt % sodiummethoxide in methanol solution (19.60 g, 101.6 mmol) was heated to 50°C. while being stirred. Into the solution, 550 g of n-hexane was addedand was stirred while being cooled to 20° C. to form a suspension. Thesuspension was separated into a precipitate and a supernatant liquidusing a pressure filter. The filtration residue was thoroughly washedwith n-hexane.

The resulting filtration residue in an amount of 35.55 g was poured into49.8 g (50.8 mmol) of an aqueous 10% phosphoric acid solution. Further,water (350 g) and 1,4-dioxane (250 g) were added, and the mixture wasallowed to react for 5 hours at 100° C. The solution was separated intotwo layers. The organic layer was separated and the aqueous layer wasextracted with toluene. The organic layer was mixed with the tolueneextract and washed with water, and then the solvent was removed bydistillation. As a result, 26.6 g of a crystal product was obtained.After isolation and purification, the crystal product was identified asmethyl 15-hydroxy-12-keto-pentadecanoate corresponding to the compoundrepresented by the general formula (7).

¹H-NMR (600 MHz, TMS, CDCl₃) 1.28 (12H, m, CH₂-4˜9), 1.57 (2H, tt,J=7.3, 7.2, CH₂-10), 1.61 (2H, tt, J=7.3, 7.0, CH₂-3), 1.84 (2H, tt,J=6.7, 6.3, CH₂-14), 2.30 (2H, t, J=7.5, CH₂-2), 2.43 (2H, t, J=7.5,CH₂-11), 2.56 (2H, t, J=6.9, CH₂-13), 3.65 (2H, t, J=6.1, CH₂-15), 3.67(3H, s, CH₃)

¹³C-NMR (150 MHz, CDCl₃) 23.86 (CH₂-10), 24.92 (CH₂-3), 26.50 (CH₂-14),29.09˜29.36 (CH₂-4˜9), 34.08 (CH₂-2), 39.48 (CH₂-13), 42.92 (CH₂-11),51.40 (CH₃), 62.33 (CH₂-OH), 174.30 (C(═O)O), 211.76 (C═O)

According to gas chromatographic determination, the crystal productcontains 79.3% of a compound represented by the general formula (7)(n=10, R=Me). The yield was 72.6% with respect to γ-butyrolactone.

Example 9

A condensation solution in an amount of 113.2 g (confirmed byquantitative analysis, after acidification of a part, that the solutioncontains 25.65 g of the condensation product and 80.84 g of theunreacted ester) prepared from dimethyl 1,12-dodecanedioate (105.00 g,406.4 mmol), γ-butyrolactone (8.75 g, 101.6 mmol), and a 28-wt % sodiummethoxide in methanol solution (19.60 g, 101.6 mmol) was heated to 50°C. while being stirred. Into the solution, 550 g of n-hexane was addedand was stirred while being cooled to 20° C. to form a suspension. Thesuspension was separated into a precipitate and a supernatant liquidusing a pressure filter. The filtration residue was thoroughly washedwith n-hexane. The resulting filtration residue in an amount of 35.55 gwas poured into 49.8 g (50.8 mmol) of an aqueous 10% phosphoric acidsolution. Further, sodium dihydrogen-phosphate anhydride (13.63 g, 96.0mmol), water (350 g) and 1,4-dioxane (250 g) were fed into the reactionvessel, and the mixture was allowed to react for 5 hours at 100° C. Thesolution was separated into two layers. The organic layer was separatedand the aqueous layer was extracted with toluene. The organic layer wasmixed with the toluene extract and washed with water, and then thesolvent was removed by distillation. As a result, 26.56 g of a crystalproduct was obtained.

According to gas chromatographic determination, the crystal productcontains 80.2% of a compound represented by the general formula (7)(n=10, R=Me). The yield was 73.3% with respect to γ-butyrolactone.

Reference Example 2

A compound represented by the general formula (7) (n=10, R=Me) (10.1 g,35 mmol), sodium hydroxide (2.80 g, 0.07 mol), and water (25.2 g) weremixed and then refluxed while being heated for 4 hours. Into themixture, 60 ml of diethylene glycol was added while continuingdistillation. One hour later, 10.3 ml of 85%-hydrated hydrazine wasadded while stirring at 110° C. for 40 minutes. The temperature of thesystem was raised to 195 to 200° C., and then stirred for 16 hours atthat temperature while removing the distilled components from thesystem. The solution was cooled, acidified with diluted sulfuric acid,and was extracted with chloroform. The chloroform layer was washed withwater and dried with anhydrous magnesium sulfate, and the solvent wasremoved by distillation. As a result, 8.92 g of crystal product mixturewas obtained.

According to gas chromatographic determination of trimethylsilylatedreaction mixture, the product mixture contains 97.2% of a compoundrepresented by the general formula (5) (n=10). The yield from thecompound represented by the general formula (1) (n=10, R=Me) was 96%.

Reference Example 3 Preparation of Reaction Mixture

A condensation solution prepared from dimethyl 1,12-dodecanedioate(105.00 g, 406.4 mmol), γ-butyrolactone (8.75 g, 101.6 mmol), and a28-wt % sodium methoxide in methanol solution (19.60 g, 101.6 mmol) washeated to 50° C. while being stirred. Into the solution, 104.4 g ofn-hexane was added, followed by stirring for 2 minutes. Next, 73.87 g ofan aqueous 5.5%-NaOH solution was added while continuing stirring for120 minutes. After the solution was allowed to stand for 5 minutes, itwas separated into an organic layer and an aqueous layer. Into theaqueous layer, 19.00 g of an aqueous 41%-NaOH solution was added. Afterrefluxing for two hours and cooling to 80° C., 126.52 g of a reactionmixture was obtained.

Example 10 Recovery of 1,18-dihydroxy-4,15-octadecanedione by Extraction

A part of the reaction mixture prepared in the above-mentioned REFERENCEEXAMPLE was extracted with the same weight of toluene for 20 minuteswhile maintaining the temperature at 80° C. This procedure was repeatedfive times, and the resulting organic layer and the aqueous layer wereindependently acidified with diluted sulfuric acid and then extractedwith ethyl acetate. After washing the organic layer with a saturatedsodium chloride solution, the solvent was distilled from the system toprepare a crystal product. Table 1 shows the results of HPLCdetermination of these layers.

TABLE 1 Results of Extraction of 1,18-dihydroxy-4,15-octadecanedionePercent by weight in the Organic Layer Aqueous layer mixture WeightRecovery Weight Recovery 15-hydroxy-12- 16.85 0.63 3.74 16.22 96.26ketopen- tadecanoic acid dodecanedioic 2.63 0.04 1.52 2.59 98.48 acid1,18-dihydroxy- 1.74 1.73 99.43 0.01 0.57 4,15- octadecanedione

Example 11 Purification of 15-hydroxy-12-ketopentadecanoic acid

The water content of the reaction mixture obtained in the REFERENCEEXAMPLE 3 was adjusted to 84%, and then the mixture was subjected tocrystallization treatment for two hours in a thermostat vessel at 40° C.The precipitated crystal product was separated into a cake and afiltrate using a centrifugal filter. Water was added to cake at 40° C.to form a slurry, and the slurry was separated into a cake and afiltrate using a centrifugal filter. The filtrate was mixed with theformer filtrate. The cake and the filtrate were acidified with dilutedsulfuric acid and extracted with ethyl acetate. After washing theorganic layer with a saturated sodium chloride solution, the solvent wasremoved by distillation to prepare a crystal product. Table 2 shows theresults of HPLC determination of these layers.

TABLE 2 Results of Extraction of 1,18-dihydroxy-4,15-octadecanedionePercent by weight in the Cake Filtrate mixture Weight Recovery WeightRecovery 15-hydroxy-12- 16.85 0 0.00 16.85 100.00 ketopen- tadecanoicacid dodecanedioic 2.63 0 0.00 2.63 100.00 acid 1,18-dihydroxy- 4,15-1.74 1.72 98.85 0.02 1.15 octadecanedione

Example 12 Purification of 15-hydroxy-12-ketopentadecanoic acid

The reaction mixture obtained in the REFERENCE EXAMPLE 3 was maintainedto 80° C., and extracted with the same weight of toluene for 20 minutes.This procedure was repeated five times, and the resulting aqueous layerwas subjected to crystallization treatment for two hours in a thermostatvessel at 20° C. The precipitated crystal product was separated into acake and a filtrate by a centrifugal filter. These were independentlyacidified with diluted sulfuric acid and extracted with ethyl acetate.After washing the organic layer with a saturated sodium chloridesolution, the solvent was removed by distillation to prepare a crystalproduct. Table 3 shows the results of HPLC determination of theselayers.

TABLE 3 Results of Purification of 15-hydroxy-12-ketopentadecanoicPercent Cake by Purity weight in Filtrate in the Recovery CrystalRecovery mixture Weight (%) (%) Weight (%) 15-hydroxy-12- 6.84 6.7298.24 98.48 0.12 1.76 ketopentadecanoic acid dodecanedioic 1.09 0.043.42 0.55 1.053 96.58 acid

The results shown in Table 3 demonstrate that the crystal productseparated before the sulfuric acid treatment 7.28 g of sodium15-hydroxy-12-ketopentadecanoate and the filtrate contains 1.25 g ofsodium dodecanedioate.

Example 13 Purification of 15-hydroxy-12-ketopentadecanoic Acid by pHAdjustment

The reaction mixture prepared in the above-mentioned REFERENCE EXAMPLE 3was extracted with the same weight of toluene for 20 minutes whilemaintaining the temperature at 80° C. This procedure was repeated fivetimes, and the resulting aqueous layer was subjected to crystallizationtreatment for 2 hours in a thermostat vessel at 20° C. The precipitatedcrystal product was separated into a cake and a filtrate using acentrifugal filter. The pH of the filtrate was adjusted to 6.5 withsulfuric acid, and the resulting crystal precipitate was separated intoa cake and a filtrate using a centrifugal filter. The pH of filtrate wasfurther adjusted to 3.0 with sulfuric acid, and a cake was obtained fromthe crystal product using a centrifugal filter. Table 4 shows theresults of HPLC determination of these cakes.

TABLE 4 Results of Purification of 15-hydroxy-12-ketopentadecanoic acidby pH Adjustment Percent Cake at pH = 6.5 by Purity Cake at pH = weightin 3.0 in the Recovery Crystal Recovery mixture Weight (%) (%) Weight(%) 15-hydroxy-12- 0.24 0.23 95.35 99.5 0.011 4.65 ketopentadecanoicacid dodecanedioic 2.11 0 0.00 0 2.11 100.00 acid

Industrial Applicability

According to the present invention,2-(ω-alkoxycarbonylalkanoyl)-4-butanolide and alkaline metal saltthereof can be obtained with high yield and satisfactory selectivity byan industrially advantageous production method using a dicarboxylateester which is inexpensive and easily obtainable.

According to the present invention, an alkaline metal salt of2-(ω-alkoxycarbonylalkanoyl)-4-butanolide and the derivative thereof,and the unreacted ester can be readily separated and purified with highyield and industrial advantages from the condensation solution obtainedby the reaction of a dicarboxylate ester and the γ-butyrolactone.

In addition, according to the present invention, a novel ester ofω-hydroxy-(ω-3)-ketoaliphatic acid is obtained at high yield and withindustrial advantages. The use of the ester ofω-hydroxy-(ω-3)-ketoaliphatic acid in the production ofω-hydroxyaliphatic acid being an important intermediate for large cycliclactone-based perfumes does not require a macro amount of alkali andfacilitates separation of water in the reaction system. Thus, a methoduseful for promoting industrial production with significantly reducedlabor is provided.

According to the present invention, α,ω-dihydroxy-δ,(ω-3)-alkanedione,ω-hydroxy-(ω-3)-ketoaliphatic acid and a salt thereof, and dicarboxylicacid and a salt thereof can be effectively recovered with highselectivity by separation in the production ofω-hydroxy-(ω-3)-ketoaliphatic acid being an important intermediate forlarge cyclic lactone-based perfumes used in the perfume industry.

What is claimed is:
 1. A method for separating and recovering an α,ω-dihydroxy-δ, (ω-3)-alkanedione represented by the general formula (9)comprising extracting the α, ω-dihydroxy-δ, (ω-3)-alkanedionerepresented by the general formula (9) with an organic solvent which isunreactive in basic conditions and insoluble in water from a mixturecontaining three compounds of an alkaline metal salt ofω-hydroxy-(ω-3)-ketoaliphatic acid represented by the general formula(5), an alkaline metal salt of a long-chain dicarboxylic acidrepresented by the general formula (8), and α,ω-dihydroxy-δ,(ω-3)-alkanedione represented by the general formula (9), or selectivelycrystallizing the α,ω-dihydroxy-δ-(ω-3)-alkanedione represented by thegeneral formula (9) from the mixture:

wherein n is an integer of 7 to 13 and M is an alkaline metal;

 wherein n is an integer of 7 to 13 and M is an alkaline metal; and

 wherein n is an integer of 7 to
 13. 2. A method for separating andrecovering an alkaline metal salt of ω-hydroxy-(ω-3)-ketoaliphatic acidrepresented by the general formula (5) and an alkaline metal salt of along-chain dicarboxylate represented by the general formula (8)comprising selectively crystallizing an alkaline metal salt ofω-hydroxy-(ω-3)-ketoaliphatic acid represented by the general formula(5) from a mixture prepared by separating and recovering an α,ω-dihydroxy-δ, (ω-3)-alkanedione represented by the general formula (9)comprising extracting the α, ω-dihydroxy-δ, (ω-3)-alkanedionerepresented by the general formula (9) with an organic solvent from amixture containing three compounds of an alkaline metal salt ofω-hydroxy-(ω-3)-ketoaliphatic acid represented by the general formula(5), an alkaline metal salt of a long-chain dicarboxylic acidrepresented by the general formula (8), and α, ω-dihydroxy-δ,(ω-3)-alkanedione represented by the general formula (9), or selectivelycrystallizing the α, ω-dihydroxy-δ, (ω-3)-alkanedione represented by thegeneral formula (9) from the mixture:

wherein n is an integer of 7 to 13 and M is an alkaline metal;

 wherein n is an integer of 7 to 13 and M is an alkaline metal; and

 wherein n is an integer of 7 to 13, of the alkaline metal salt ofω-hydroxy-(ω-3)-ketoaliphatic acid represented by the general formula(5) and the alkaline metal salt of long-chain dicarboxylic acidrepresented by the general formula (8) and separating the mixture into acake and a filtrate by solid-liquid separation.
 3. A method forseparating and recovering an α, ω-dihydroxy-δ, (ω-3)-alkanedionerepresented by the general formula (9) according to claim 1, wherein theorganic solvent is selected from the group of benzene, toluene, xylenet,tetraline, decalin, pentane, hexane, heptane, octane, cyclohexane,isopropyl ether and dibutyl ether.
 4. A method for separating andrecovering an α, ω-dihydroxy-δ, (ω-3)-alkanedione represented by thegeneral formula (9) according to claim 1, wherein the organic solvent istoluene.